Process of preparing amino-compounds of the steroid series



Patented Oct. 13, 1953 PROCESS OF PREPARING AMINO-M- POUNDS or THESTEROID scams Josef Schmidt-Thom, Frankfurt am Main Uriterliederba'c'lr,

Germany, assignorto- Farbwerke Hoechst Akt'ien'gesellschaft vormalsMeister Lucius and Briining, Frankfurt am Main Hochs't, Germany, aGerman, company No Drawing. Application March 22, 1952,- Serial InGermany March 30,1951.

6 Claims. (01. zen-397.55)

The present invention relates to the manufacture of compounds having thecharacter 01' the male sexual hormones-.-

Inmy application Ser. No. 278,131, filed March 22, 1952 and entitledProcess of Preparing Amino-Compounds of the Steroid Series is describeda process for the manufacture of 17- acetyl-amino-compouiids of thecyclopentanopolyhydrophenanthrene series by subjecting 20- oximes of thesaid series to the Beckmann re-arrangement with the aid of phosphorusoxy'chloride and pyridine.

An object of the present invention is to provide a process for thehydrolysis of l7=acetylaminocompounds of theeyclopentano-polyhydrophenanthrene series so as to obtain thecorresponding 17-amines.

In U. S. specification No. 2,212,363 is described a process for makingamines of the cyclopentanopolyhydrophenanthrene series inv whichcompounds of the said series containing in the 1'7- position the group NCH OHa-group are subjected to the Beckmann re-arrangement. There-arrangement isbrought about by'treating the oxime with thionylchloride in solution in benzene. There are also mentioned asre-arrangement agents phosphorus pentachloride and sulfuric acid. The17-acetylamino-compounds so obtained are not isolated, but are converteddirectly into the 17-amines by hydrolysis with strong acids. The yieldsof the amines amount to about 30 per cent.- I

The small yields of theamines are probably due mainly to the fact thatthe steroidsare not resistant to strong acids during long reactionperiods and at high temperatures, and that'side reactions may occurduring hydrolysis in an acid medium. In U. S. specification No.2,531,441 it is stated that it'is not possible in practiceto hydrolyze17- acetylamino-compounds. This statement does not conflict with thestatements in the specification No. 2,212,363, since the acid hydrolysisdescribed therein is not suitable foruse on an industrial scale owing tothe long duration of the heating, and, as stated above, side reactionsoccur. In Example 19 of the aforesaid U. S. specification theparatoluene sulfonate of 3B-acetoxy- A -pregnene-20-one-oxime, afterre-a'rrangement with dilute sulfuric acid and being already partiallyhydrolyzed in 3-position, is treated with a solution of potassiumhydroxide in methanol,

wherebyhydrolysls in the 3-position alone is completed. The 17-acetylgroup is not attacked. Even during the subsequent heating of thecompound with ethanolamine, a strongly basicsu-bstance, no hydrolysisoccurs in the 17-po'sition, and the unaltered, starting material isrecovered.

The present invention is based on the observation that1-7-acetylamino-compounds of the 0y.- clopentano-polyhydrophenanthreneseries, which contain a hydroxyl or acetylatedhydroxyl group as asubstituent in the 3-position, can be hydrolysed very readily withinorganic, alkaline substances at a temperature above 95 C. The freel'l-amines are obtained from the 1'7-acetylami'nes in a yield exceedingper cent.

The hydrolysis of the l'I-acet'ylainines with inorganicalkalinesubstances may be carriedv out either in solvents boiling above0., advantageously monoliydric or, polyhydric alcohols, such as n-butylalcohol, amyl alcohol, isoamyl alcohol, ethylene glycol, propyleneglycol, glycerin or the ike, or organic bases, such as ethanolamine,quinoline or the like. Alternatively, the hydrolysis may be carried outin an autoclave with the addition of a monohydric or polyhydri'calcohol, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amylor isoamyl alcohol, ethylene. glycol, propylene glycol or glycerin, oran organic base, such asethanolamine, pyridine, quinoline or the like asa solvent.

The hydrolysis, takes place at temperatures above 95 C.,, advantageouslyat, a temperature above C. Suitable inorganic alkaline substances arealkaline earth hydroxides, alkali carbonates and above all alkalihydroxides. They are advantageously used in a concentration of 15 to 20per cent.- If, for example, an. alcoholic solution of sodium hydroxideof 20 per cent. strength is used in a closed vessel at a temperature of160 C.-"C., and the duration of the heating is 3 hours, the free17-amine is obtained from 17-acetylamine in a yield exceeding 90 percent. The same yield is obtained by boilingfor 2 hours in a solution of15 per cent. strength of potassium hydroxide in ethylene glycol.

The free 17-amines may be prepared as such and isolated. As, however,they are sometimes obtained in an oily form, it is of advantage toisolate them in the form of their salts. This may be carried out, forexample, by adding an ethereal solution of an acid to an etherealsolution'of the amine. The amine salt then precipitates. Organic orinorganic acids may be used for the precipitation, for example, aceticacid, oxalic acid, 'succinic acid, benzoic acid, phthalic acid, sulfuricacid, hydrochloric acid, perchloric acid or the like.

The free amines can easily be recovered from the salts by mixing thelatter in an alcoholic solution with alkali and pouring the mixture intowater. The amine, which separates, can then be isolated by filtrationand washed with water or extracted with ether.

The compounds of the invention are useful as medicaments or asintermediate products for the preparation of medicaments.

The following examples serve to illustrate the invention but they arenot intended to limit it thereto:

Example 1 700 milligrams of 3 S-acetoxy-17-acetylamino- A -androsteneare suspended in 20 cc. of alcohol, a solution of 3 grams of sodiumhydroxide in 10 cc. of water is added, and the mixture is heated for 4hours at 180 C. in a closed copper tube or in a V2-steel tube. Thereaction solution is poured into water, the product is extracted withether, and the ethereal solution is washed with water, dried andconcentrated by evaporation. When a small portion of glacial acetic acidis added, the acetate of Be-hydroxy-l'l-amino- A -androsteneprecipitates. The yield amounts to 620 milligrams (95 per cent. of thetheoretical yield) and the product melts at 227-230 C. (uncorrected).The product may be recrystallized from a mixture of alcohol and ethylacetate, and is then obtained in the form of fine needles. Instead ofsodium hydroxide, the corresponding quantity of potassium hydroxide maybe used equally well. Instead of ethyl alcohol, there may be usedmethyl, propyl or isopropyl alcohol or a polyhydric alcohol, such asethylene glycol or glycerin. An organic base, such as pyridine,ethanolamine or the like, may also be used as solvent, in which case thereaction temperature and the period of reaction must, if required, beincreased.

The free hydroxy-amine base can be obtained from the salt or directlyfrom the hydrolysis solution as follows:

1 gram of the acetate of 3fl-hydroxy-l'7-amino- A -androstene issuspended in methanol. By the addition of a few drops of caustic sodasolution complete dissolution is brought about. The solution is thenpoured into water. The precipitate which is initially finely flocculentcan be readily filtered after being allowed to stand for a short time.After drying on the water-bath, 860 milligrams of crudelid-hydroxy-17-amino-A -androstene (95 per cent. of the theoreticalyield) are obtained. The product is recrystallized from dilute methanolin the form of laminae melting at 162 C. (uncorrected).

The free amine may be isolated directly in the hydrolysis, as follows:

2 grams of 3B-acetoxy-l'l-acetylamino-A -androstene are hydrolyzed asdescribed above in a closed steel tube. The reaction solution is pouredinto water, and the reaction product which separates in the form offlocks is filtered off and thoroughly washed with water. 1.45 grams ofcrude BB-hydroxy-l'l-amino-A -androstene are obtained. The product meltsat 162 C. (uncorrected). The yield amounts to 91 per cent of thetheoretical yield.

The crude compound may be purified as follows:

500 milligrams of crude 3p-hydroxy-1'I-amino- A -androstene aredissolved in 5 cc. of alcohol, and 0.2 cc. of freshly distilledbenzaldehyde are added. After a few seconds crystals begin to separate.After minutes the crystals are separated by filtration. 550 milligramsof the benzal compound are obtained melting at 232 C. Afterrecrystallization from butyl acetate the product melts at 234 C.(uncorrected).

The benzal compound may be split again as follows:

200 milligrams of the benzala-mine so obtained are suspended in 5 cc. ofalcohol and 0.5 cc. of concentrated hydrochloric acid is added,whereupon dissolution occurs at once. The mixture is boiled for 10minutes and lamellae of Bfi-hydroxyl'l-amino-A -androstene hydrochlorideseparate. After cooling, the hydrochloride is filtered off. To convertit into the free amine it is suspended in a small quantity of methanoland a few drops of sodium hydroxide solution are added. The crystals ofthe hydrochloride dissolve, and then 3B- hydroxy l7 amino A androstenecrystallizes. The product is identified by the mixed melting pointmethod.

Example 2 1 gram of 3e-hydroxy-I'I-acetylamino-A -androstene is heatedin a mixture of cc. of alcohol and 3 grams of sodium hydroxide(dissolved in 5 cc. of water) in a closed tube for 4 hours at 160-180 C.The reaction solution is then poured into water, extracted with etherand the ethereal solution is washed with water, dried and concentratedto about 100 cc. On adding a small quantity of a solution of oxalic acidin ether, the oxalate of 3,8 hydroxy 1'7 amino A androsteneprecipitates.

Example 3 250 milligrams of 3,3-acetoxy-l'l-acetylaminoandrostane in amixture of 10 cc. of alcohol and 1.25 g. of sodium hydroxide (dissolvedin 2.5 cc. of water) are heated for 2 hours in a closed copper tube at180 C. The reaction solution is poured into water and the whiteprecipitate which separates is filtered off with suction, washed withwater and dried. 180 milligrams of lie-hydroxyl'I-amino-androstane areobtained melting at 150 C. The yield amounts to per cent. of thetheoretical yield. As the product recrystallizes sparingly frommethanol, it is dissolved in ether, and the ethereal solution, afterbeing dried, is concentrated by evaporation and mixed with a few dropsof glacial acetic acid. The acetic acid salt which precipitates at oncemelts at 217 C. (uncorrected). After repeated recrystallization from amixture of methanol and ethyl acetate, the pure acetate of3fi-hydroxy-l'l-aminoandrostane is obtained in the form of lamellarcrystals which melt at 228 C. (uncorrected).

Example 4 1.8 grams of 3fl-acetoxy-l'l-acetylamino-A androstene areheated at the boil for 3 hours under reflux in cc. of glycol togetherwith 15 grams of potassium hydroxide. The solution is then poured intowater and extracted with ether. The ethereal solution is washed withwater, dried with sodium sulfate, concentrated to about 100 cc. andgradually mixed with acetic acid. 1.5 grams of the acetate of3,8-hydroxy-17-amino-A androstene precipitate. It melts at 227 C.(uncorrected). Instead of the potassium hydroxide there may be used thecorresponding quantity of sodium hydroxide. Instead of glycol, there mayExample 5 500 milligrams of 3;3hydroxy-17-acetylamino- A -androstene areheated at the boil for 2 hours in a reflux apparatus in a solution of 5grams of potassium hydroxide in 30 cc. of ethylene glycol. A smallcontent of water is not detrimental, but the boiling point of thesolvent mixture must be higher than 180 C. The reaction mixture ispoured into water, the precipitate, which separates in the form offlocks, is filtered oil and washed with water. After recrystallizationfrom methanol, 370 milligrams (85 per cent. of the theoretical yield) ofSp-hydroxy-l'l-amino-A androstene are obtained; the product melts at 160C. (uncorrected). It is not essential to carry out the hydrolysis at theboiling temperature. Thus, the hydrolysis may be conducted at atemperature below the boiling point, but then the period of the reactionis correspondingly increased. Thus, for example, heating for 4 hours at180 C. is necessary.

The acetylamine may also be hydrolyzed with sodium hydroxide orpotassium hydroxide in butanol, but in this case the period required forthe reaction is substantially increased.

I claim:

1. The process of producing amino compounds of the steroid series whichcomprises hydrolyzing 1'7-acetylamino compounds of the formulaRNH'CO'CH3 wherein R is a cyclopentanopolyhydrophenanthrene radical,which is substituted in position 3 by a member of the group consistingof hydroxyl and acylated hydroxyl by means of an inorganic,

strong alkaline substance at a temperature above 2. The processaccording to claim 1, which comprises hydrolyzing 17- acetylaminecompounds of the formula wherein R is acyclopentanopolyhydrophenanthrene radical, which is substituted inposition 3 by a. member of the group consisting of hydroxyl and acylatedhydroxyl by means of an inorganic, strong alkaline substance at atemperature above 95 C. and at an elevated pressure.

3. The process according to claim 1, which comprises hydrolyzing 17acetylamine compounds of the formula wherein R is acyclopentanopolyhydrophenanthrene radical, which is substituted inposition 3 by a member of the group consisting of hydroxyl and acylatedhydroxyl by means of an inorganic, strong alkaline substance at atemperature above 95 C. and at atmospheric pressure.

4. The process according to claim 1, which comprises hydrolyzing 3pacetoxy 17 acetylamino-androstene by means of an inorganic, strongalkaline substance at a temperature above 95 C.

5. The process according to claim 1, which comprises hydrolyzing 3phydroxy 17 acetylamino-androstene by means of an inorganic, strongalkaline substance at a temperature above 95 C.

6. The process according to claim 1. which comprises hydrolyzing 3,8acetoxy 17 acetylamino-androstane by means of an inorganic, strongalkaline substance at a temperature above 95 C.

JOSEF SCHMIDT-THOME.

No references cited

1. THE PROCESS OF PRODUCING AMINO COMPOUNDS OF THE STEROID SERIES WHICHCOMPRISES HYDROLYZING 17-ACETYLAMINO COMPOUNDS OF THE FORMULA